Role of the hyperpolarization-activated current Ih in somatosensory neurons.
The hyperpolarization-activated current (I(h)) is an inward current activated by hyperpolarization from the resting potential and is an important modulator of action potential firing frequency in many excitable cells. Four hyperpolarization-activated, cyclic nucleotide-modulated subunits, HCN1-4, can form I(h) ion channels. In the present study we investigated the function of I(h) in primary somatosensory neurons. Neuronal firing in response to current injection was promoted by elevating intracellular cAMP levels and inhibited by blockers of I(h), suggesting that I(h) plays a critical role in modulating firing frequency. The properties of I(h) in three size classes of sensory neurons were next investigated. In large neurons I(h) was fast activating and insensitive to elevations in cAMP, consistent with expression of HCN1. I(h) was ablated in most large neurons in HCN1(-/-) mice. In small neurons a slower activating, cAMP-sensitive I(h) was observed, as expected for expression of HCN2 and/or HCN4. Consistent with this, I(h) in small neurons was unchanged in HCN1(-/-) mice. In a neuropathic pain model HCN1(-/-) mice exhibited substantially less cold allodynia than wild-type littermates, suggesting an important role for HCN1 in neuropathic pain. This work shows that I(h) is an important modulator of action potential generation in somatosensory neurons.
Momin
Aliakmal
A
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
Cadiou
Hervé
H
Mason
Adrian
A
McNaughton
Peter A
PA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D048429:Cell Size; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000166:cytology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007546:Isoquinolines / Q000494:pharmacology; D008610:Menthol / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000378:metabolism
D054815:Cyclic Nucleotide-Gated Cation Channels; C578666:Hcn1 protein, mouse; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007546:Isoquinolines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; C082246:ICI D2788; D008610:Menthol; D005576:Colforsin; D000242:Cyclic AMP; D015232:Dinoprostone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide